The present invention concerns macrocyclic aminophosphonic acid complexes for the treatment of cancer, especially the treatment of calcific tumors and for the relief of bone pain, the method of treatment of calcific tumors, and compositions and formulations having as their active ingredient a radionuclide complexed with a macrocyclic aminophosphonic acid.
The development of bone metastasis is a common and often catastrophic event for a cancer patient. The pain, pathological fractures, frequent neurological deficits and forced immobility caused by these metastatic lesions significantly decrease the quality of life for the cancer patient. The number of patients that contract metastatic disease is large since nearly 50% of all patients who contract breast, lung or prostate carcinoma will eventually develop bone metastasis. Bone metastasis are also seen in patients with carcinoma of the kidney, thyroid, bladder, cervix and other tumors, but collectively, these represent less than 20% of patients who develop bone metastasis. Metastatic bone cancer is rarely life threatening and occasionally patients live for years following the discovery of the bone lesions. Initially, treatment goals center on relieving pain, thus reducing requirements for narcotic medication and increasing ambulation. Clearly, it is hoped that some of the cancers can be cured.
The use of radionuclides for treatment of cancer metatastic to the bone dates back to the early 1950's. It has been proposed to inject a radioactive particle-emitting nuclide in a suitable form for the treatment of caldific lesions. It is desirable that such nuclides be concentrated in the area of the bone lesion with minimal amounts reaching the soft tissue and normal bone. Radioactive phosphorus (P-32 and P-33) compounds have been proposed, but the nuclear and biolocalization properties limit the use of these compounds. [See for example, Kaplan, E., et al., Journal of Nuclear Medicine 1(1), 1 (1960) and U.S. Pat. No. 3,965,254.]
Another attempt to treat bone cancer has been made using phosphorus compounds containing a boron residue. The compounds were injected into the body (intravenously) and accumulated in the skeletal system. The treatment area was then irradiated with neutrons in order to activate the boron and give a therapeutic radiation dose. (See U.S. Pat. No. 4,399,817).
The use of radionuclides for calcific tumor therapy is discussed in published European patent application 176,288 where the use of Sm-153, Gd-159, Ho-166, Lu-177 or Yb-175 complexed with certain ligands selected from ethylenediaminetetraacetic acid (EDTA) or hydroxyethylethylenediaminetriacetic acid (HEEDTA) is disclosed.
In the above mentioned procedure, it is not possible to give therapeutic doses to the tumor without substantial damage to normal tissues. In many cases, especially for metastatic bone lesions, the tumor has spread throughout the skeletal system and amputation or external beam irradiation is not practical. (See Seminars in Nuclear Medicine, Vol. IX, No. 2, April, 1979).
The use of Re-186 complexed with a diphosphonate has also been proposed. [Mathieu, L. et al., Int. J. Applied Rad. & Isotopes 30, 725-727 (1979); Weinenger, J. Ketring, A. R., et al., Journal of Nuclear Medicine 24(5), 125 (1983)]. However, the preparation and purification needed for this complex limits its utility and wide application.
Strontium-89 has also been proposed for patients with metastatic bone lesions. However, the long half-life (50.4 days), high blood levels and low lesion to normal bone ratios limit the utility. [See Firusian, N., Mellin, P., Schmidt, C. G., The Journal of Urology n116, 764 (1976); Schmidt, C. G., Firusian, N., Int. J. Clin. Pharmacol. 93, 199-205, (1974).]
A palliative treatment of bone metastasis has been reported which employed I-131 labeled .alpha.-amino-(3-iodo-4-hydroxybenzylidene)diphosphonate [Eisenhut, M., Journal of Nuclear Medicine 25(12), 1356-1361 (1984)]. The use of radioactive iodine as a therapeutic radionuclide is less than desirable due to the well known tendency of iodine to localize in the thyroid. Eisenhut lists iodide as one of the possible metabolites of this compound.
Surprisingly, the present invention overcomes many of the above noted problems. The present invention concerns at least one composition comprising a radionuclide complexed with a macrocyclic aminophosphonic acid, such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylenephosphonic acid or its physiologically acceptable salt, which composition causes minimal damage to normal tissue when administered in the method of the invention. Surprisingly, the present complex is more effective at a lower ligand to metal molar ratio than has been known previously in the art.